Effects of cyclosporin-A on immune response, tissue protection and motor function of rats subjected to spinal cord injury

Ibarra, Antonio; Correa, Dolores; Willms, Kaethe; Merchant, Marie Thêrese; Guı́zar-Sahagún, Gabriel; Grijalva, Israel; Madrazo, Ignacio

doi:10.1016/s0006-8993(03)02898-1

Cited by 64 publications

(63 citation statements)

References 66 publications

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“…In addition, a recently completed clinical study reported that CsA administration resulted in a smaller infarct size in patients undergoing percutaneous coronary intervention [99]. However, a role for CsA as a neuroprotective agent in experimental models of acute SCI is inconclusive due to conflicting reports regarding its efficacy [105][106][107][108][109][110].…”

Section: Targeting the Mptp In Acute Scimentioning

confidence: 99%

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

et al. 2011

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Summary: Traumatic injury to the mammalian spinal cord is a highly dynamic process characterized by a complex pattern of pervasive and destructive biochemical and pathophysiological events that limit the potential for functional recovery. Currently, there are no effective therapies for the treatment of spinal cord injury (SCI) and this is due, in part, to the widespread impact of the secondary injury cascades, including edema, ischemia, excitotoxicity, inflammation, oxidative damage, and activation of necrotic and apoptotic cell death signaling events. In addition, many of the signaling pathways associated with these cascades intersect and initiate other secondary injury events. Therefore, it can be argued that therapeutic strategies targeting a specific biochemical cascade may not provide the best approach for promoting functional recovery. A "systems approach" at the subcellular level may provide a better strategy for promoting cell survival and function and, as a consequence, improve functional outcomes following SCI. One such approach is to study the impact of SCI on the biology and function of mitochondria, which serve a major role in cellular bioenergetics, function, and survival. In this review, we will briefly describe the importance and unique properties of mitochondria in the spinal cord, and what is known about the response of mitochondria to SCI. We will also discuss a number of strategies with the potential to promote mitochondrial function following SCI.

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Section: Targeting the Mptp In Acute Scimentioning

confidence: 99%

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

et al. 2011

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“…Few hours after injury, ischemia and infarction are the first secondary events to develop, these cause clinical features, such as, the lack of sensitivity and mobility. Other well-studied detrimental mechanisms that are involved in secondary damage are: lipid peroxidation, excitotoxicity, activation of the apoptotic cascade, ionic dysregulation, inflammation and the activation of an autoreactive response against neural constituents [2,3]. Regarding the latter, it has been shown that SCI induces the stimulation of immune components against neural selfantigens.…”

Section: Introductionmentioning

confidence: 99%

Autoreactivity against myelin basic protein in patients with chronic paraplegia

et al. 2011

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Introduction Previous studies have shown the existence of either cellular or humoral MBP-reactive elements up to 5 years after spinal cord injury (SCI), but not the presence of both after 10 years. Materials and methods Twelve SCI patients, with more than 10 years of evolution, and 18 healthy blood donors were studied. Lymphocyte proliferation (colorimetricBrdU ELISA assay) and antibody titers against MBP (ELISA Human IgG MBP-specific assay) were assessed. Results SCI patients presented a significant T-cell proliferation against MBP (lymphocyte proliferation index: 3.7 ± 1.5, mean ± SD) compared to control individuals (0.7 ± 0.3; P \ 0.001). Humoral response analysis yielded a significant difference (P \ 0.0001) between the antibody titers of controls and SCI patients. A significant correlation between cellular and humoral responses was observed. Finally, patients with an ASIA B presented the highest immune responses. Conclusion This work demonstrates, for the first time, the existence of both cellular and humoral responses against MBP in the chronic stages ([10 years) of injury.

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“…8 After spinal cord compression, CsA treatment improves motor performance but does not increase the extent of spared tissues. 7 Conversely, no improvement in motor performance, or in the amount of spared cord tissue, is reported after spinal cord contusion when CsA is administered before, during or after injury. [9][10] In our model of compression injury, CsA treatment did not have a neuroprotective effect, as it did not modify the functional recovery and the lesion extension.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, CsA has been reported to be neuroprotective following SCI. 6 Rats subjected to spinal compression 7 or contusion 8 present a better motor outcome when treated with CsA. However, in other studies, absence of CsA neuroprotection at both behavioral and morphological levels was reported after SCI.…”

Section: Introductionmentioning

confidence: 94%

Potential adverse effects of cyclosporin A on kidneys after spinal cord injury

et al. 2010

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Study design: Cell transplantation strategies are gaining increasing interest for spinal cord injury (SCI) with the objective of promoting spinal cord repair. To avoid allogenic graft rejection, an adequate immune suppression is required, and one of the most potent and commonly used immunosuppressives is cyclosporin A (CsA). In SCI, permanent sensory motor loss is combined with modifications of drug absorption, distribution and elimination. Objectives: The objectives of this study were to thoroughly explore histological and functional outcomes of CsA treatment in a rat model of spinal cord compression. Setting: Experiments were carried out at the Institute for Neurosciences of Montpellier (France), the Integrative Biology of Neurodegeneration Laboratory (Spain) and in the Novartis Institutes for BioMedical Research (Switzerland) for CsA blood concentration determination. Methods: We first evaluated histological outcomes of CsA treatment on kidneys and spinal cord after SCI. We then investigated whether SCI modified CsA blood concentration. Finally, using behavioral analysis, we assessed the potential CsA impact on functional recovery. Results: When spinal-cord-injured rats were treated with a CsA dose of 10 mg kg À1 per day, we observed deleterious effects on kidneys, associated with modifications of CsA blood concentration. Adding an antibiotic treatment reduced kidney alteration without modifying CsA blood concentration. Finally, we showed that CsA treatment per se modified neither functional recovery nor lesion extension. Conclusion: This study pinpoints the absolute requirement of careful CsA monitoring in the clinical setting for patients with SCI to minimize potential unexpected effects and avoid therapeutic failure.

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Effects of cyclosporin-A on immune response, tissue protection and motor function of rats subjected to spinal cord injury

Cited by 64 publications

References 66 publications

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

Targeting Mitochondrial Function for the Treatment of Acute Spinal Cord Injury

Autoreactivity against myelin basic protein in patients with chronic paraplegia

Potential adverse effects of cyclosporin A on kidneys after spinal cord injury

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